Mixing- Powders & Granules

Chapter 6 of Text – pg 168-88

Mixing – powders and
granules
In order to produce pharmaceutical
tablets and capsules, formulation
mixes must be made that will allow us
to use modern, state of the art
production equipment in order to
convert these mixes into quality
finished dosage forms.
Therefore, the quality of the finished
dosage form depends on the quality of
the mix
Powder mixing and flow
Lots of factors influence mixing andsubsequent
flow from one container to another:

 Adhesion
 Cohesion
 Particle shape
 Particle size
 Surface properties (eg static)
 Humidity
 Density
 etc
Mixing processes

 Why do we have to mix materials?

 1/ to provide a homogeneous blend to

make capsules or tablets – every
tablet or capsule of the same dosage
type must contain the exact* amount of
drug substance ( *ie be within the
allowable limits)
Mixing

 2/ to provide a blend that will flow well

in the process allowing for production
of tablets or capsules at high speeds
which results in good content
uniformity
 Mixing: the distribution of individual
particles uniformly amongst all other
ingredients
What is needed to provide a good
mix?

 All of the particles need to be of the

same particle size and density or they
will not mix properly
 Try mixing marbles and tennis balls
together – can you ever achieve a
good mix?
 Only particles of similar sizes and
densities can provide a good mix
Particle size
 Dimensions of particulate solids is important
in the manufacture and in the physical and
pharmacological performance of the drug
 Both tablets and capsules are produced
using equipment that controls the amount of
the mix by volumetric filling

 A certain predetermined volume of powder

will flow into either the tablet dye or the
empty capsule shell in order to produce the
final dosage form
Particle size

 Irregular particle sizes have different

flow and packing properties – particles
can become segregated (separated)
from other particles
 This interferes with the uniformity of fill
volume and reduces content uniformity
of the drug (API particles segregated
from excipients or visa-versa)
Particle size

 different particle sizes can also alter

the volume of powder during an
encapsulation or tablet compression
event
 Therefore must closely define and
control particle size
Particle size

 When patient takes medication,

absorption of the drug depends on its
release into solution
 This is also affected by particle size
(which relates to surface area)
 Smaller particles, greater surface area
– dissolve faster (greater diffusion and
dissolution), greater potential
bioavailability
Particle size

 Small particles not always beneficial –

in one case (nitrofurantoin) the
increased rate of dissolution caused
toxic effects because the drug was
absorbed too quickly
 Knowledge and control of particle size
important in both manufacture and in
efficacy of the drug
Particle size

Influence of Particle Size:

- Dissolution rate
- Uniformity of distribution of particles
within mixes
- Physical manufacturing of final product
- Penetrability of particles – i.e. inhalers
- Grittiness of particles in smooth
preparations - unpleasant
Particle size

 Particles are not usually completely

spherical or regularly shaped
 Particle “diameter” can be defined in a
few different ways
 Can use simple techniques – use a
circle with the particles dimensions to
approximate its size
 Can also use sedimentation
times/volumes or other physical
properties
Particle size

 Particle size distribution is also

important
 (remember Gaussian distributions in
stats?)
 Want a narrow distribution – also want
a normal distribution (can get skewed
or bimodal (coarse and fines))
Particle size

The purpose of Particle size

determination is to gather data on the
size, distribution and shapes of
particles.
Particle size characterization and control
is fundamental to effective
pharmaceutical development and
manufacture
Particle size

For this reason, screening and sieving is

performed on powders/granules in
order to help assure certain particle
size and consistency
Particle size analysis-methods

 1/ Sieve methods
 Particles are passed through a series
of sieves of known and successively
smaller pore openings
 Amount of powder passing through or
not indicates granule size
 Not easy to automate sieving methods
Particle size analysis
 2/ microscopic methods
 Light microscope or scanning electron
microscopy (gives 3D image)
 Particles visually measured

 3/ laser light scattering

 Based on diffraction and angle of
diffraction of laser light by the particles
Particle size analysis
 3/ cont.d.. Particle size influences amount of
light reaching a sensor as particles pass
through the sensing zone

 4/ Sedimentation methods
 Speed of particle settling either based on
gravity or centrifugation
 How fast do the particles settle out of a
liquid medium?
 Faster settling means what particles?
Particle size reduction

 We usually want to reduce particle size

 May be needed in order to facilitate
powder mixing or to produce proper
suspensions
 May want to reduce bulk volume of
powder to improve transport efficiency
 Ease of size reduction (comminution)
depends on the physical nature
(brittleness or plasticity) of the material
Surface hardness
 Size reduction also relies on surface
hardness (described in Mohs scale –
ranking of hardness from diamond (>7) to
talc (<3) – materials at top of scale can
scratch the surface of materials lower down)
 Hard materials are harder to comminute
leading to abrasive wear on metal mill parts
leading to product contamination
 Plastic materials (eg rubber) are very soft
but very difficult to size reduce
Surface hardness

 Rubbers, gums, waxy materials (eg

stearic acid) can absorb large amounts
of energy through elastic and plastic
deformation without breaking down
into smaller particles
 Often must lower temperature (below
glass transition) to make them brittle
enough to crush
Particle size reduction

 Only about 2% of energy input actually

goes into size reduction
 Can easily have uneven milling or size
reduction since different size particles
are more susceptible to breaking
 Really small particles can actually
increase in size through agglomeration
due to pressure and other forces
involved
Size reduction methods
Particle size reduction

 Many different types

 Size reduction depends on milling time

Definition -
Comminution: reduction of the particle size of a solid
substance to a finer state. The reduction of the PS
results in an increase in the surface area of the
substance, which increases solubilization, aids in
formulation and manufacture and enhances
Bioavaliability.
Cutting methods
 Cutter mills – series of knives attached to a
horizontal rotor which act against a series of
stationary knives on the mill itself
 Particles fracture between two sets of knives
(clearance of a few mm’s)
 A screen retains the particles until they are
small enough to fall out
 High shear rates – useful to produce coarse
degree of size reduction of dried granules
and also of fibrous crude drugs (eg roots,
peels, barks) prior to extraction
Compression methods

 Eg a mortar and pestle on a small

scale

 Mechanized large mortar and pestle

arrangements – rarely used currently
Impact methods
 Hammer mill
 Series of hammers hinged on a central shaft
– swing out radially from rotating shaft
 Velocity of hammers cause particles to
undergo brittle fracture
 Breaks large particles more effectively than
small ones – produces powders with a
narrow size range
 Screen once again retains particles until
they reach a certain size (dictated by the
screen)
Hammermill
Attrition methods

 Roller mills
 Porcelain or metal rollers with an
adjustable gap (as small as 20 um)
 Rollers rotate at different speeds so
that material is sheared as it passes
through the gap
Ball mills

 Hollow cylinder rotated on its axis

 Balls fill cylinder to about 30-50% of its
volume
 Use large and small balls to
completely contact the powder
Ball Mill
Size reduction

 Different mills give different products

from the same starting material
 Different particle shape, proportion of
fines
Screening

 Use a mill and screen – most common

 Size of particle depends on size
screen used
 Higher screen number = finer the
screenings = smaller particles
 Can screen ingredients to provide
similar sized particles of each
Screening equipment commonly
used

 The oscillating granulator

 The Fitzmill
 The Comill
 The Bar Rotor
Fitzmill
Comill
Oscillating granulator
Particle size separation

 Have to select particle size range we

want for our application
 Can classify powders into several
particle ranges
 Sieving
 Sedimentation
 Cyclone methods
What makes up a typical mix?

 The API – the active pharmaceutical

ingredient
 The other ingredients – excipients
What makes up a typical mix?

Powder characteristics which affect mixing:

- Size and distribution of particles

- Shape of particles

- Density of particles

- Friability of particles

- Cohesiveness of particles

- Hygroscopicity of particles (water pick-up)

What makes up a typical mix?

A typical powder mixture: 5 Primary

ingredients - Active
- Diluent
- Binder
- Disintegrant
- Lubricant
What makes up a typical mix?

Secondary ingredients - Glidant

- Absorbant
- Color
- Preservative
- Flavour
Typical mix

 The filler/binder
 Alone or in combination
 Low cost, consistent quality – makes
up bulk of tablets, binds particles
together
 Eg lactose, microcrystalline cellulose,
calcium phosphate dibasic,
pregelatinized starch, modified
sucrose, other sugars
Typical mix

 Binders for wet granulations

 Vegetable gums
 Cellulose derivatives
 Liquid glucose/sucrose
 Starch (as a paste)
 Sodium alginate
Typical mix

 The glidant

 Silicon dioxide
 Starch
 Makes granulation slippery so that it
will flow during production of tablets or
caps – into dyes, caps shells, into
hoppers, etc
Typical mix

 The lubricant

 Metal stearates (zinc, calcium,

magnesium)
 Starch
 Prevent granulation from sticking to
rollers, machinery or tablet press
(punches)
Typical mix

 Disintegrant

 Starch, carboxymethylcellulose

 What is the purpose of the

disintegrant?
Types of mixes

 Direct mixes for Direct Compression

 Simplest type of mix

 Easiest and fastest process
 Final mix is free flowing and can be
directly encapsulated or tabletted
Mechanisms of mixing and
demixing

 Powders:

 Powder particles must move relative to one

another
 Three main mechanisms:
 1/ convection (eg mixer paddle or blade)
 2/ shear mixing (one layer moves over
another)
 3/ diffusive mixing (particles fall through
voids)
Segregation or demixing
 Components can tend to settle out
 Very important concern in pharmaceuticals
 Must avoid segregation during handling after
powders have been mixed
 Eg during transfer steps to filling machines or in
hoppers
 Increases content variation
 Occurs since not all particles are identical in shape,
size and density
 Can select API and excipients based on particle
size to minimize this (different processing steps to
obtain each)
Planetary mixer
High Shear Mixer
Types of mixes

 Often when mix powders together they form

a mixture which is not suitable for
processing
 Must be free flowing

 Produce granulations of powders

 Increases material density leading to better
flow properties
 Also compresses better in tabletting
machinery
Granulation - Purpose

 To produce uniform blends/mixtures

 To produce uniform particle size
 To control dusts
 To improve flow properties
 To control bulk density
 To control particle hardness
 To improve solution or dispersion rates
Granulation

There are three main methods of

producing formulations/ dry powders
mixes for manufacture
1) Direct Blending (aka Direct
Compression
2) Dry Granulation

3) Wet Granulation
Granulation

1. Direct Blending
- Simplest and easiest of the three
methods
- Components may need to be milled
and screened first – why?
- Dry ingredients blended together

- Final mix (blend) is lubricated (how?)1.

Granulation

Direct blending is the first choice

because its easy and economical but it
isn’t always suitable for all formulations
Amount of API in the mix, physical and
chemical nature of particles in mix
(morphology, density, etc) may make
homogeneous mix hard to achieve
Granulation

2. Dry Granulation: A process whereby

particles are formed into granules
which aid in powder flow, homogeneity
and reduced particle segregation

Granulation produces particles of similar

sizes
Granulation

Process involves dry mixing/ blending the

formuation powders, compacting this
mix into slugs or crude tablet forms,
milling (grinding) or sizing to reduce
these slugs back to particulate , final
blending of the “new” mix, and the
lubrication.
Dry granulation

 Powder mixture compacted into large

pieces
 Then broken down and sized into
granules
 The active or the diluent must have
some cohesive properties for this to
work
Dry granulation

 “slugging” – weigh and mix ingredients

 Slugged or compressed into large
“tablets” about 1” in diameter
 Slugs then broken up and “screened”
for sizing
 Lubricant added and tablets prepared
Dry granulation

 Roller compaction may be used in

place of “slugging”
 Powder mixture is pressed between
high pressure rollers at 1-6 tons
pressure
 Called chilsonating using a chilsonator
 Then broken up, sized and
compressed into tablets, etc.
Wet granulation

3. Wet Granulation : A process whereby

powder mixtures (formulations) are
dampened or wet massed with a solvent
(that usually contains binders) and then
mixed to develop granules
Granules are dried, milled to size and blended
with remaining formulation to form the “final
blend” for tabletting or encapsulation
Wet granulation
 Sometimes dry granulation is
unsuccessful
 Dry granulation is long involved
process
 Must “wet” the mix with an appropriate
solvent (eg water)
 Make a granule (still wet)
 Dry the mix, resize and finally remix
granules with lubricant and
disintegrant
Wet granulation
 Advantages:
 Can be the only way

 Disadvantages
 Cost of drying ovens and tray dryers is high
(energy) – note fluid bed technology
 Exposure of API and other ingredients to liquid and
heat – can be harmful to stability
 Disintegration and Dissolution becomes two step
process to release the primary drug particles from
the formulation – so what?
Wet granulation

 Can do in separate steps as described

on last slide or use a fluid bed
granulator which performs all of the
processes in one piece of equipment